This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as allergic diseases and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1,-2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1xcex1, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d) [I-309, TARC, MIP-1xcex2] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: 
wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR6CONHR7, wherein R6 and R7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 95/13069 is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general formula: 
wherein A may be substituted alkyl or Z-substituted alkyl, with Zxe2x95x90NR6a or O. Compounds of this type are claimed to promote the release of growth hormone in humans and animals.
WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-hydroxytryptamine (5-HT) agonists and antagonists: 
wherein A is lower alkylene and R4 may be phenyl optionally substituted with halogen.
U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonists comprising 1,4-dihydropyridines with a piperidinyl or tetrahydropyridinyl-containing moiety attached to the 3-position of the 4-phenyl ring: 
wherein B may be NH, NR1, O, or a bond, and R7 may be substituted phenyl, benzyl, phenethyl and the like.
Patent publication EP 0 903 349 A2 discloses CCR-3 receptor antagonists comprising cyclic amines of the following structure: 
wherein T and U may be both nitrogen or one of T and U is nitrogen and the other is carbon and E may be xe2x80x94NR6CONR5xe2x80x94 and others.
These reference compounds are readily distinguished structurally by either the nature of the urea functionality, the attachment chain, or the possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidines and pyrrolidines as having activity toward the chemokine receptors.
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein A, G, R1, R4, R4xe2x80x2, R5, R17, n and u are defined below, are effective modulators of chemokine activity.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula (I): 
xe2x80x83or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
A is selected from 
G is selected from xe2x80x94C(O)R3, xe2x80x94C(O)NR2R3, xe2x80x94C(O)OR3, xe2x80x94SO2NR2R3, xe2x80x94SO2R3, xe2x80x94C(xe2x95x90S)NR2R3, C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, C(xe2x95x90C(CN)2)NR2R3, 
W, at each occurrence, is independently selected from C or N, provided at least two of W are C;
X is selected from O, S, and NR19;
X1 and X2 are independently selected from C and N;
Z1 is selected from C and N;
Z2 is selected from NR1a, O, S and C;
R1 and R2 are independently selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 Ra;
R1a is independently selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 Ra;
Ra, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNRbRb, (CH2)rOH, (CH2)rORc, (CH2)rSH, (CH2)rSRc, (CH2)rC(O)Rb, (CH2)rC(O)NRbRb, (CH2)rNRbC(O)Rb, (CH2)rC(O)ORb, (CH2)rOC(O)Rc, (CH2)rCH(xe2x95x90NRb)NRbRb, (CH2)rNHC(xe2x95x90NRb)NRbRb, (CH2)rS(O)pRc, (CH2)rS(O)2NRbRb, (CH2)rNRbS(O)2Rc, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
Rc, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered ring substituted with 0-3 Ra;
R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3xe2x80x2R3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3xe2x80x2 and R3xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 Ra;
alternatively, R4 joins with R8 or R11 to form a pyrrolidine or piperidine ring system substituted with 0-3 R4d;
R4xe2x80x2 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4axe2x80x2, (CH2)qC(O)OR4a, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4c;
R4a and R4axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
R4d, is selected from H, C1-6 alkyl, (CHRxe2x80x2)qOH, (CHRxe2x80x2)qOR7a, (CHRxe2x80x2)qOC(O)R7b, (CHRxe2x80x2)qOC(O)NHR7a;
R5 is selected from a (CR5xe2x80x2R5xe2x80x3)txe2x80x94C3-10310 carbocyclic residue substituted with 0-5 R1616 and a (CR5xe2x80x2R5xe2x80x3)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R1616;
R5xe2x80x25 and R5xe2x80x35, at each occurrence, are selected from H, C1-616 alkyl, (CH22)rC3-636 cycloalkyl, and phenyl;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHRxe2x80x2)qOH, (CHRxe2x80x2)qSH, (CHRxe2x80x2)qOR7d, (CHRxe2x80x2)qSR7d, (CHRxe2x80x2)qNR7aR7axe2x80x2, (CHRxe2x80x2)qC(O)OH, (CHRxe2x80x2)rC(O)R7b, (CHRxe2x80x2)qC(O)NR7aR7axe2x80x2, (CHRxe2x80x2)qNR7aC(O)R7a, (CHRxe2x80x2)qNR7aC(O)H, (CHRxe2x80x2)qC(O)OR7a, (CHRxe2x80x2)qOC(O)R7b, (CHRxe2x80x2)qS(O)pR7b, (CHRxe2x80x2)qS(O)2NR7aR7axe2x80x2, (CHRxe2x80x2)qNR7aS(O)2R7b, (CHRxe2x80x2)qNHC(O)NR7axe2x80x2R7a, (CHRxe2x80x2)qNHC(O)OR7a, (CHRxe2x80x2)qOC(O)NHR7a, C1-6 haloalkyl, a (CHRxe2x80x2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CHRxe2x80x2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
R7a and R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR7fR7f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR7fR7f, (CH2)rNR7fC(O)R7a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R7b, (CH2)rC(xe2x95x90NR7f)NR7fR7f, (CH2)rS(O)pR7b, (CH2)rNHC(xe2x95x90NR7f)NR7fR7f, (CH2)rS(O)2NR7fR7f, (CH2)rNR7fS(O)2R7b, and (CH2)rphenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R7e, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)qOH, OH, (CH2)qSH, SH, (CH2)rSC1-5 alkyl, (CH2)qNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8a;
R8a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or xe2x95x90NR8b;
R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR11d, (CH2)qSR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11b, (CH2)qNR11aC(O)NR11axe2x80x2R11a, (CH2)rC(O)OR11a, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11axe2x80x2, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(xe2x95x90NR11f)NR11fR11f, (CH2)rNHC(xe2x95x90NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R11e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O) (CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(xe2x95x90NR15f)NR15aR15axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR15f)NR15aR15axe2x80x2, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R15e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f, and (CH2)rphenyl;
R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(xe2x95x90NR16f)NR16aR16axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR16f)NR16aR16axe2x80x2, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16aand R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R16e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R17, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR17d, (CH2)qSR17d, (CH2)qNR17aR17axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R17b, (CH2)rC(O)NR17aR17axe2x80x2, (CH2)qNR17aC(O)R17b, (CH2)qNR17aC(O)H, (CH2)rC(O)OR17a, (CH2)qOC(O)R17b, (CH2)qS(O)pR17b, (CH2)qS(O)2NR17aR17axe2x80x2, (CH2)qNR17aS(O)2R17b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R17c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R17c;
R17a and R17axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R17e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R17e;
R17b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R17e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R17e;
R17c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR17fR17f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R17b, (CH2)rC(O)NR17fR17f, (CH2)rNR17fC(O)R17a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R17b, (CH2)rC(xe2x95x90NR17f)NR17fR17f, (CH2)rS(O)pR17b, (CH2)rNHC(xe2x95x90NR17f)NR17fR17f, (CH2)rS(O)2NR17fRl7f, (CH2)rNR17fS(O)2R17b, and (CH2)rphenyl substituted with 0-3 R17e;
R17d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R17e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R17c;
R17e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR17fR17f, and (CH2)rphenyl;
R17f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R18, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHRxe2x80x2)qOH, (CHRxe2x80x2)qSH, (CHRxe2x80x2)qOR18d, (CHRxe2x80x2)qSR18d, (CHRxe2x80x2)qNR18aR18axe2x80x2, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)R18b, (CHRxe2x80x2)rC(O)NR18aR18axe2x80x2, (CHRxe2x80x2)qNR18aC(O)R18a, (CHRxe2x80x2)qNR18aC(O)H, (CHRxe2x80x2)rC(O)OR18a, (CHRxe2x80x2)qOC(O)R18b, (CHRxe2x80x2)qS(O)pR18b, (CHRxe2x80x2)qS(O)2NR18aR18axe2x80x2, (CHRxe2x80x2)qNR18aS(O)2R18b, C1-6 haloalkyl, a (CHRxe2x80x2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R18c, and a (CHRxe2x80x2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R18c;
R18a and R18axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R18e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R18e;
R18b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R18e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R18e;
R18c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR18fR18f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R18b, (CH2)rC(O)NR18fR18f, (CH2)rNR18fC(O)R18a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R18b, (CH2)rC(xe2x95x90NR18f)NR18fR18f, (CH2)rS(O)pR18b, (CH2)rNHC(xe2x95x90NR18f)NR18fR18f, (CH2)rS(O)2NR18fR18f, (CH2)rNR18fS(O)2R18b, and (CH2)rphenyl substituted with 0-3 R18e;
R18d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R18e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R18c;
R18e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR18fR18f, and (CH2)rphenyl;
R18f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R19 is selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, xe2x80x94C(O)R19b, xe2x80x94C(O)NR19aR19a, xe2x80x94C(O)OR19a, and xe2x80x94SO2R19a, a (CHRxe2x80x2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R16, and a (CHRxe2x80x2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16;
R19a is selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-6 cycloalkyl, a (CR5xe2x80x25R5xe2x80x3)t-C3-10310 carbocyclic residue substituted with 0-5 R1516 and a (CR5xe2x80x25R5xe2x80x35)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R1616;
R19b is selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-6 cycloalkyl, a (CR5xe2x80x2R5xe2x80x3)t-C3-10310 carbocyclic residue substituted with 0-5 R1516 and a (CR5xe2x80x2R5xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R1616;
m, at each occurrence, is selected from 1, 2, 3, 4, and 5;
n, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
o, at each occurrence, is selected from 1 and 2;
p, at each occurrence, is selected from 1 and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
q, at each occurrence, is selected from 1, 2, 3, 4, and 5;
s, at each occurrence, is selected from 0, 1, and 2;
t, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
u, at each occurrence, is independently selected from 0, 1, and 2;
v, at each occurrence, is selected from 0 and 1; and
w, at each occurrence, is selected from 0, 1, 2, and 3.
[2] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R4xe2x80x2 is absent or, taken with the nitrogen to which it is attached to form an N-oxide;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHRxe2x80x2)qOH, (CHRxe2x80x2)qOR7d, (CHRxe2x80x2)qNR7aR7axe2x80x2, (CHRxe2x80x2)qC(O)R7b, (CHRxe2x80x2)qC(O)NR7aR7axe2x80x2, (CHRxe2x80x2)qNR7aC(O)R7b, (CHRxe2x80x2)qNR7aC(O)H, (CHRxe2x80x2)qS(O)2NR7aR7axe2x80x2, (CHRxe2x80x2)qNR7aS(O)2R7b, (CHRxe2x80x2)qNHC(O)NHR7a, (CHRxe2x80x2)qNHC(O)OR7a, (CHRxe2x80x2)qOC(O)NHR7a, C1-6 haloalkyl, a (CHRxe2x80x2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CHRxe2x80x2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or xe2x95x90NR8b;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qOR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11b, (CH2)qNR11aC(O)NHR11a, (CH2)qNHC(O)NHR11a, (CH2)qNHC(O)OR11a, (CH2)qOC(O)NHR11a, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c.
[3] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
A is selected from 
t is selected from 0, 1, and 2.
[4] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R17 is selected from H; and
R18 is selected from H.
[5] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
A is selected from 
[6] In another, the present invention provides novel compounds of formula (I) wherein:
G is selected from xe2x80x94C(O)R3, xe2x80x94C(O)NR2R3, xe2x80x94C(O)OR3, xe2x80x94SO2NR2R3, and xe2x80x94SO2R3, xe2x80x94C(xe2x95x90S)NR2R3, C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, C(xe2x95x90C(CN)2)NR2R3, and 
[7]. In another embodiment, the present invention provides novel compounds of formula (I), wherein:
G is selected from xe2x80x94C(O)NR2R3, 23C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, and C(xe2x95x90C(CN)2)NR2R3;
[8] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R16, at each occurrence, is selected from methyl, ethyl, propyl, iso-propyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, methyl, ethyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R16e;
R16e, at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF3, and OCH3;
R16f, at each occurrence, is selected from H; and
r is selected from 0, 1, and 2.
[9] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R15 and a (CR3xe2x80x2CR3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, subsituted with 0-2 R15;
R3xe2x80x2 and R3xe2x80x3, , at each occurrence, are selected from H;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2) C(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15fR15f, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is selected from H, and C1-6 alkyl;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e; and
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, (CF2)rCF3, and OH.
[10] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
G is selected from 
[11] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R1 is selected from H;
both X1 and X2 cannot be C; and
Z2 is selected from NR1xe2x80x2, O, and S.
[12] In a further embodiment, the present inveniton provides novel compounds of formula (I), wherein:
R16, at each occurrence, is selected from methyl, ethyl, propyl, iso-propyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, methyl, ethyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R16e;
R16e, at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF3, and OCH3;
R16f, at each occurrence, is selected from H; and
r is selected from 0, 1, and 2.
[13] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15fR15f, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is selected from H, and C1-6 alkyl;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e; and
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, (CF2)rCF3, and OH.
[14] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
A is selected from 
v is selected from 0 and 1.
[15] In another embodiment, the present invention provides novel compounds of formula (I) wherein:
G is selected from xe2x80x94C(O)R3, xe2x80x94C(O)NR2R3, xe2x80x94C(O)OR3, xe2x80x94SO2NR2R3, and xe2x80x94SO2R3, xe2x80x94C(xe2x95x90S)NR2R3, C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, C(xe2x95x90C(CN)2)NR2R3, and 
[16]. In another embodiment, the present invention provides novel compounds of formula (I), wherein:
G is selected from xe2x80x94C(O)NR2R3,23 C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, and C(xe2x95x90C(CN)2)NR2R3.
[17] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R16, at each occurrence, is selected from methyl, ethyl, propyl, iso-propyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, methyl, ethyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R16e;
R16e, at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF3, and OCH3;
R16f, at each occurrence, is selected from H; and
r is selected from 0, 1, and 2.
[18] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R15 and a (CR3xe2x80x2CR3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, subsituted with 0-2 R15 
R3xe2x80x2 and R3xe2x80x3, at each occurrence, are selected from H;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is selected from H, and C1-6 alkyl;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e; and
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, (CF2)rCF3, and OH.
[19] In a further embodiment, the prsent invention provides novel compounds of formula (I), wherein:
G is selected from 
[20] In a further embodiment, the present invention provides novel compounds of formula (I), wherein:
R1 is H;
both X1 and X2 cannot be C; and
Z2 is selected from NR1xe2x80x2, O, and S.
[21] In a further embodiment, the present invention provides novel compounds of formula (I), wherein:
R16, at each occurrence, is selected from methyl, ethyl, propyl, iso-propyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, methyl, ethyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R16e;
R16e, at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF3, and OCH3;
R16f, at each occurrence, is selected from H; and
r is selected from 0, 1, and 2.
[22] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is selected from H, and C1-6 alkyl;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R15e; and
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, (CF2)rCF3, and OH.
[23] In a further embodiment, the present invention provides novel compounds of formula (I), wherein the compound of formula I is selected from:
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea hydrochloride;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea hydrochloride;
N-(3-cyanophenyl)-Nxe2x80x2-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea trifluoroacetate;
N-(3-cyanophenyl)-Nxe2x80x2-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea trifluoroacetate;
N-(3-cyanophenyl)-Nxe2x80x2-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]urea trifluoroacetate;
N-(3-cyanophenyl)-Nxe2x80x2-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]urea trifluoroacetate;
N-(3-acetylphenyl)-Nxe2x80x2-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]urea trifluoroacetate;
N-(3-acetylphenyl)-Nxe2x80x2-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]urea trifluoroacetate;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(4-fluorophenyl)-Nxe2x80x2-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(4-fluorophenyl)-Nxe2x80x2-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(4-fluorophenyl)-Nxe2x80x2-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(4-fluorophenyl)-Nxe2x80x2-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;
N-(3-acetylphenyl)-Nxe2x80x2-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)urea;
N-(3-acetylphenyl)-Nxe2x80x2-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;
N-(3-acetylphenyl)-Nxe2x80x2-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;
N-(3-acetylphenyl)-Nxe2x80x2-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;
N-(3-acetylphenyl)-Nxe2x80x2-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;
N-(3-acetylphenyl)-Nxe2x80x2-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;
N-(3-acetylphenyl)-Nxe2x80x2-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;
N-(3-acetylphenyl)-Nxe2x80x2-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea; and
N-(3-acetylphenyl)-Nxe2x80x2-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.
[24] In a third embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
[25] In a fourth embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
[26] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
[27] In another embodiment, the present invention provides a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, G is selected from xe2x80x94C(O)R3, xe2x80x94C(O)NR2R3, xe2x80x94C(O)OR3, xe2x80x94SO2NR2R3, xe2x80x94SO2R3, xe2x80x94C(xe2x95x90S)NR2R3, C(xe2x95x90NR1a)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, C(xe2x95x90C(CN)2)NR2R3, 
In another embodiment, G is selected from xe2x80x94C(O)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, and C(xe2x95x90C(CN)2)NR2R3.
In another embodiment, G is selected from xe2x80x94C(O)NR2R3.
In another embodiment, G is selected from 
In another embodiment, R1, R1xe2x80x2, and R2 are equal to H.
In another embodiment, R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R15 and a (CR3xe2x80x2CR3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, subtituted with 0-3 R15.
In another embodiment, R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R15.
In another embodiment, R3 is phenyl substitued with 0-2 R15.
In another embodiment, R4 is absent.
In another embodiment, R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1-10 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. C2-10 alkenyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. C2-10 alkynyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6,and C7 cycloalkyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw, where v=1 to 3 and w=1 to (2v+1)).
As used herein, the term xe2x80x9c5-6-membered cyclic ketalxe2x80x9d is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e. g. , solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount alone or in combination with other active ingredients or an amount the combination of compounds claimed effective to modulate chemokine receptor activity or treat the symptoms of asthma or an allergic disorder in a host.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated in their entirety by reference.
The novel compounds of Formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of Formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must be used. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for the protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups in Organic Chemistry, Wiley and Sons, 1991). 
Compounds of Formula I may be prepared as shown in Scheme 1. Compounds in which D is a bond, O or NR1 may be synthesized by reacting Formula II with Formula III, wherein Z is a good leaving such as but not limited to Cl, Br, or imidazole, in the presence of a base such as, but not limited to, triethylamine or pyridine. Alternatively, Formula II may be reacted with an isocyanate of Formula V to provide compounds of Formula I where G is CONHR3. Alternatively, Formula II may be reacted with Formula IV, wherein Z is a good leaving group such as but not limited to Cl, Br, or imidazole, in the presence of a base such as, but not limited to, triethylamine or pyridine to provide compounds of Formula I where G is SO2R3. Alternatively, Formula II may be reacted with Formulas VI, VII, or VIII wherein Z is a good leaving group such as but not limited to ethoxide, phenoxide, or methylsulfide to provide compounds of Formula I according to procedures described in Hoffman, et. al. J. Med. Chem. 1983, 26, 140 and references therein. 
Alternatively, compounds of Formula I can be synthesized by coupling compounds of Formula II with halogenated heterocycles of Formula IX as described in Scheme 2. It is understood that the chemistry is shown for only one heterocycle and that similar transformations may be preformed on other halogenated heterocycles. This procedure essentially follows the general procedures of Hong, Y. et. al., Tet. Lett. 1997, 38, 5607 and references therein, with minor modification depending on the Formula IX which should be readily recognized by one skilled in the art. The reaction can be preformed in an inert solvent such as, but not limited to, toluene at room temperature to the reflux temperature of the solvent with a Pd-catalyst such as Pd2(dba)3 and a base such as sodium t-butoxide. The halogenated heterocycles that are not commercial available can be synthesized by methods known in the art and are exemplified by, but not limited to, Zou. R. , J. Med Chem. 1997, 40, 802. 
Compounds of Formula II, where R1 is not hydrogen, may be prepared by procedures depicted in Scheme 3. Reductive alkylation of Formula X with an aldehyde or ketone is carried out under conditions known in the art, for example, catalytic hydrogenation with hydrogen in the presence of palladium or platinum or with reducing agents such as sodium triacetoxyborohydride. Alternatively, a similar transformation can be accomplished with an alkylating agent R1Z where Z is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. in the presence of a base such as triethylamine, pyridine, etc. in acetonitrile, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent. 
Compounds of Formula X, where R4 is not hydrogen, may be prepared by procedures depicted in Scheme 4. Reductive alkylation of Formula XI with an aldehyde or ketone is carried out under conditions known in the art, for example, catalytic hydrogenation with hydrogen in the presence of palladium or platinum or with reducing agents such as sodium triacetoxyborohydride. Alternatively, a similar transformation can be accomplished with an alkylating agent R4Z where Z is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. in the presence of a base such as triethylamine, pyridine, etc. in acetonitrile, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent. The protecting group (P) can then be removed using the appropriate reagents, well familiar to one skilled in the art, and typical examples may be found in Greene, T and Wuts, P. G. M. , Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. , New York, N.Y., 1991 and references therein, to provide intermediates of Formula X. 
Compounds of Formula X, where R4 is hydrogen, or Formula XI may be prepared by procedures depicted in Scheme 5. Reductive alkylation of Formula XIII with a cyclic ketone of Formula XII can be carried out under conditions known in the art, for example, catalytic hydrogenation with hydrogen in the presence of palladium or platinum or with reducing agents such as sodium triacetoxyborohydride. Compounds of Formula XIII that are not commercially available can be synthesized by methods known in the art and are exemplified by, but not limited to, Guan et. al., Synlett 1999, 426, Skarzewski and Gupta Tetrahedron: Asymmetry, 1997, 8, 1861, Bitha, and Lin, J. Heterocycl. Chem. 1988, 25, 1035, Ohba et. al., Agric. Biol. Chem. 1974, 38, 2431, and Toftlund, and Pedersen, Acta Chem. Scand., 1972, 26, 4019. 
Compounds of Formula XII may be prepared by procedures depicted in Scheme 6. This procedure essentially follows the general protocols of Mitra and Joshi, Synth. Commun., (1988), 18, 2259 and references therein, with minor modification depending on R5 which should be readily recognized by one skilled in the art. The cycloalkenones can be treated with grinard reagents in the presence of copper chloride to incorporate R5 to produce compounds of Formula XII. Alternatively, monoprotected cyclic diketones can be treated under wittig reaction conditions, well known to one skilled in the art, and then hydrogenated and deprotected to produce compounds of Formula XII. Other methods for producing compounds of Formula XII can be found in the reference Lednicer et. al., J. Med. Chem. 1972, 15, 1239.
The compounds of this invention and their preparation can be understood further by the following working examples, which do not constitute a limitation of the invention.